Multiple myeloma is a neoplastic disease characterized by infiltration of bone and bone marrow by myeloma cells forming multiple tumor masses that lead to pathological fractures. The condition is usually progressive and fatal. Symptoms include anemia, renal damage and high globulin levels in blood and increased susceptibility to bacterial infections. The impaired abnormal immunoglobulin production observed in multiple myeloma may be due to the presence of a monocyte or macrophage that suppresses the maturation of normal B-lymphocytes into antibody secreting cells. Life expectancy is related to extent of the disease at diagnosis and response to treatment. The median life expectancy of responding patients is two years. High levels of myeloma protein in serum or urine, bone lesions, hypercalcemia, pancytopenia, and renal failure are unfavorable signs.
Although Multiple Myeloma remains incurable, the development of novel therapies has dramatically increased response rates and survival over recent years. Despite major advances in our understanding of this complex disease, a standard remission-induction therapeutic approach is taken to patients in similar categories of age and performance status in the great majority of treatment centers. High dose chemotherapy with autologous stem cell transplant remains the standard therapy for younger patients.
Monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma are the most frequent forms of monoclonal gammopathies. Monoclonal gammopathy of undetermined significance is the most common plasma cell dyscrasia with an incidence of up to 10% of population over age 75. The molecular basis of monoclonal gammopathy of undetermined significance and multiple myeloma are not very well understood and it is not easy to differentiate the two disorders. The diagnosis of multiple myeloma or monoclonal gammopathy of undetermined significance is identical in ⅔ of cases using classification systems that are based on a combination of clinical criteria such as the amount of bone marrow plasmocytosis, the concentration of monoclonal immunoglobulin in urine or serum, and the presence of bone lesions. Especially in early phases of multiple myeloma, the differential diagnosis is associated with a certain degree of uncertainty.
Furthermore, in the diagnosis of multiple myeloma, the clinician must exclude other disorders in which a plasma cell reaction may occur such as rheumatoid arthritis and connective tissue disorders, or metastatic carcinoma where the patient may have osteolytic lesions associated with bone metastases. Therefore, given that multiple myeloma is thought to have an extended latency and clinical features are recognized many years after the development of the malignancy, new molecular diagnostic techniques are needed in screening for the disease and providing differential diagnosis for multiple myeloma. Thus, there is a need for new and accurate methods for differentially diagnosing and identifying distinct and prognostically relevant clinical subgroups of multiple myeloma.
Complicating the search for such new methods is the fact that multiple myeloma cells are endowed with a multiplicity of anti-apoptotic signaling mechanisms that account for their resistance to current chemotherapy and thus the ultimately fatal outcome for most patients. While aneuploidy by interphase fluorescence in situ hybridization (FISH) and DNA flow cytometry are observed in >90% of cases, cytogenetic abnormalities in this typically hypoproliferative tumor are informative in only about 30% of cases and are typically complex, involving on average seven different chromosomes. It has therefore been difficult to establish correlations between genetic abnormalities and clinical outcomes.
Consequently, given the unreliability of individual gene expression within multiple myeloma tumor cells, there exists a need for a biomarker whose measurement can not only predict the likelihood that an individual has multiple myeloma and will likely benefit from anticancer therapies, but is also useful for determining whether individuals or subpopulations of individuals who are currently in remission following successful anticancer therapy for multiple myeloma are likely to suffer relapse. Such a marker would be helpful for guiding health care professionals involved in the treatment of an individual suffering from or thought to have multiple myeloma. Consequently, a marker of this sort would be useful not only for diagnostic purposes, but also to track prognosis following the initiation of treatment and establishment of remission.
This invention provides such a biomarker and uses the expression and subcellular localization of non-coding mitochondrial RNAs (ncmtRNAs) within plasmocytes isolated from bone marrow to select individuals or subpopulations of individuals who will benefit from an anti-multiple myeloma therapy as well as to identify individuals in remission who are likely to relapse or who have relapsed following remission.
Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles) are referenced. The disclosure of all patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety for all purposes.